The evolutionary path of chemosensory and flagellar macromolecular machines in Campylobacterota.

The evolution of macromolecular complex is a fundamental biological question, which is related to the origin of life and also guides our practice in synthetic biology. The chemosensory system is one of the complex structures that evolved very early in bacteria and displays enormous diversity and complexity in terms of composition and array structure in modern species. However, how the diversity and complexity of the chemosensory system evolved remains unclear. Here, using the Campylobacterota phylum with a robust "eco-evo" framework, we investigated the co-evolution of the chemosensory system and one of its important signaling outputs, flagellar machinery. Our analyses show that substantial flagellar gene alterations will lead to switch of its primary chemosensory class from one to another, or result in a hybrid of two classes. Unexpectedly, we discovered that the high-torque generating flagellar motor structure of Campylobacter jejuni and Helicobacter pylori likely evolved in the last common ancestor of the Campylobacterota phylum. Later lineages that experienced significant flagellar alterations lost some key components of complex scaffolding structures, thus derived simpler structures than their ancestor. Overall, this study revealed the co-evolutionary path of the chemosensory system and flagellar system, and highlights that the evolution of flagellar structural complexity requires more investigation in the Bacteria domain based on a resolved phylogenetic framework, with no assumptions on the evolutionary direction.

Expression pattern of serum interleukin-7 in elderly septic patients and its prognostic value for predicting short-term mortality.

BACKGROUND: The identification of novel prognostic biomarkers in elderly septic patients are essential for the improvement of mortality in sepsis in the context of precision medicine. The purpose of this study was to explore the expression pattern and prognostic value of serum interleukin-7 (IL-7) in predicting 28-day mortality in elderly patients with sepsis. METHODS: Patients were retrospectively enrolled according to the sepsis-3.0 diagnostic criteria and divided into the survival group and non-survival group based on the clinical outcome at the 28-day interval. The baseline characteristic data, samples for the laboratory tests, and the SOFA, Acute Physiology and Chronic Health Evaluation (APACHE II), as well as Glasgow coma scale (GCS) scores, were recorded within 24 h after admission to the emergency department. Serum levels of IL-7 and TNF-α of the patients were quantified by the Luminex assay. Spearman correlation analysis, logistic regressive analysis and receiver operating characteristic curve (ROC) analysis were performed, respectively. RESULTS: Totally, 220 elderly patients with sepsis were enrolled, 151 of whom died in a 28-day period. Albumin (ALB), high-density lipoprotein (HDL), systolic pressure (SBP), and platelet (PLT) were found to be significantly higher in the survival group (p < 0.05). IL-7 was shown to be correlated with TNF-α in the non-survival group (p = 0.030) but not in the survival group (p = 0.194). No correlation was shown between IL-7 and other factors (p > 0.05). IL-7 and TNF-α were found to be independent risk factors associated with the 28-day mortality (OR = 1.215, 1.420). Combination of IL-7, SOFA and ALB can make an AUROC of 0.874 with the specificity of 90.77 %. Combination of IL-7 and TNF-α can make an AUROC of 0.901 with the sensitivity of 90.41 % while the combination of IL-7, TNF-α, and ALB can make an AUROC of 0.898 with the sensitivity of 94.52 %. CONCLUSIONS: This study highlights the importance of monitoring the serum level of IL-7 and TNF-α in elderly septic patients as well as evaluating the combinations with other routine risk factors which can be potentially used for the identification of elderly septic patients with higher risk of mortality.

Predictive value of soluble CD40L combined with APACHE II score in elderly patients with sepsis in the emergency department.

BACKGROUND: The prognostic performance of soluble CD40L (sCD40L) for illness severity in infectious diseases is rarely reported. We investigated the ability of sCD40L combined with Acute Physiology and Chronic Health Evaluation II (APACHE II) score to evaluate mortality in septic patients in the emergency department(ED). METHODS: We enrolled 222 septic patients in the ED of Beijing Chao-Yang Hospital from October 2020 to April 2021. Their serum sCD40L, PCT, lactate (Lac), Sequential Organ Failure Assessment (SOFA) score, Acute Physiology and Chronic Health Evaluation II (APACHE II) score were used to predict the prognosis of septic patients in terms of 28-day mortality. Serum sCD40L was detected by Human XL Cytokine Luminex. Logistic regression analysis and receiver operating characteristic (ROC) curves were used to assess the prognostic value of the variables. RESULTS: One hundred ninety-five patients met the inclusion criteria, divided into survival group (55 cases) and non-survival group (140 cases). sCD40L, PCT, Lac, SOFA and APACHE II score were found to independently predict 28-day mortality (P < 0.05). The AUC values of sCD40L, PCT, Lac, SOFA and APACHE II score were 0.662,0.727,0.704, 0.719 and 0.716, respectively. There was no difference in the diagnostic value of sCD40L compared with the PCT, Lac, SOFA score or APACHE II score (Z1 = 1.19, P = 0.234; Z2 = 0.77, P = 0.441; Z3 = 1.05, P = 0.294; Z4 = 0.97, P = 0.332). However, the combined evaluation of sCD40L + APACHE II (AUC:0.772, Z = 2.10, P = 0.036) was much better than sCD40L alone in predicting 28-day mortality. CONCLUSION: The predictive value of sCD40L + APACHE II is better than sCD40L alone for 28-day mortality. sCD40L combined with APACHE II score is valuable for predicting 28-day mortality in elderly patients with sepsis.

Palmitoylation landscapes across human cancers reveal a role of palmitoylation in tumorigenesis.

BACKGROUND: Protein palmitoylation, which is catalyzed by palmitoyl-transferase and de-palmitoyl-transferase, plays a crucial role in various biological processes. However, the landscape and dynamics of protein palmitoylation in human cancers are not well understood. METHODS: We utilized 23 palmitoyl-acyltransferases and seven de-palmitoyl-acyltransferases as palmitoylation-related genes for protein palmitoylation analysis. Multiple publicly available datasets were employed to conduct pan-cancer analysis, examining the transcriptome, genomic alterations, clinical outcomes, and correlation with c-Myc (Myc) for palmitoylation-related genes. Real-time quantitative PCR and immunoblotting were performed to assess the expression of palmitoylation-related genes and global protein palmitoylation levels in cancer cells treated with Myc depletion or small molecule inhibitors. Protein docking and drug sensitivity analyses were employed to predict small molecules that target palmitoylation-related genes. RESULTS: We identified associations between palmitoylation and cancer subtype, stage, and patient survival. We discovered that abnormal DNA methylation and oncogenic Myc-driven transcriptional regulation synergistically contribute to the dysregulation of palmitoylation-related genes. This dysregulation of palmitoylation was closely correlated with immune infiltration in the tumor microenvironment and the response to immunotherapy. Importantly, dysregulated palmitoylation was found to modulate canonical cancer-related pathways, thus influencing tumorigenesis. To support our findings, we performed a proof-of-concept experiment showing that depletion of Myc led to reduced expression of most palmitoylation-related genes, resulting in decreased global protein palmitoylation levels. Through mass spectrometry and enrichment analyses, we also identified palmitoyl-acyltransferases ZDHHC7 and ZDHHC23 as significant contributors to mTOR signaling, DNA repair, and immune pathways, highlighting their potential roles in tumorigenesis. Additionally, our study explored the potential of three small molecular (BI-2531, etoposide, and piperlongumine) to modulate palmitoylation by targeting the expression or activity of palmitoylation-related genes or enzymes. CONCLUSIONS: Overall, our findings underscore the critical role of dysregulated palmitoylation in tumorigenesis and the response to immunotherapy, mediated through classical cancer-related pathways and immune cell infiltration. Additionally, we propose that the aforementioned three small molecule hold promise as potential therapeutics for modulating palmitoylation, thereby offering novel avenues for cancer therapy.

Comparative Genomic Insights into Chemoreceptor Diversity and Habitat Adaptation of Archaea.

Diverse archaea, including many unknown species and phylogenetically deeply rooted taxa, survive in extreme environments. They play crucial roles in the global carbon cycle and element fluxes in many terrestrial, marine, saline, host-associated, hot-spring, and oilfield environments. There is little knowledge of the diversity of chemoreceptors that are presumably involved in their habitat adaptation. Thus, we have explored this diversity through phylogenetic and comparative genomic analyses of complete archaeal genomes. The results show that chemoreceptors are significantly richer in archaea of mild environments than in those of extreme environments, that specific ligand-binding domains of the chemoreceptors are strongly associated with specific habitats, and that the number of chemoreceptors correlates with genome size. The results indicate that the successful adaptation of archaea to specific habitats has been associated with the acquisition and maintenance of chemoreceptors, which may be crucial for their survival in these environments. IMPORTANCE Archaea are capable of sensing and responding to environmental changes by several signal transduction systems with different mechanisms. Much attention is paid to model organisms with complex signaling networks to understand their composition and function, but general principles regarding how an archaeal species organizes its chemoreceptor diversity and habitat adaptation are poorly understood. Here, we have explored this diversity through phylogenetic and comparative genomic analyses of complete archaeal genomes. Signaling sensing and adaptation processes are tightly related to the ligand-binding domain, and it is clear that evolution and natural selection in specialized niches under constant conditions have selected for smaller genome sizes. Taken together, our results extend the understanding of archaeal adaptations to different environments and emphasize the importance of ecological constraints in shaping their evolution.

Sex hormone levels in females of different ages suffering from depression.

BACKGROUND: There are only a few studies on sex hormones in females of different ages suffering from depression, and their conclusions are not uniform until now. This study aimed to investigate the correlation between the severity of depression in females and factors such as sex hormones and differences in sex hormone levels in females of different ages, exploring variations after treatment. METHODS: A total of 169 females with depression were selected and divided into the first-episode (91 cases) and recurrent (78 cases) groups. Then, on the basis of their age, the first-episode patients were divided into the young (48 cases, age < 45 years), perimenopausal (20 cases, 45-55 years), and elderly groups (23 cases, age > 55 years); the patients with recurrent depression were classified into the young (37 cases, age < 45 years), perimenopausal (19 cases, 45-55 years), and elderly groups (22 cases, age > 55 years). The patients were assessed in accordance with the International Classification of Diseases of mental and behavioral disorders. The serum progesterone, prolactin, estradiol, and testosterone levels in the patients were measured, and differences in sex hormone levels of the groups were analyzed. RESULTS: The estradiol level was negatively correlated with age and the prolactin level was positively correlated with occupation. The severity of depression in females was found to be negatively correlated with age. The serum progesterone and estradiol levels in the young group were significantly higher than those in the elderly group, regardless of the first episode or recurrence. Estradiol levels in the perimenopausal and elderly groups with first-episode depression were significantly higher than those in the same group with recurrent depression. However, there was no significant difference in the serum progesterone, prolactin, estradiol, and testosterone levels in the recurrent group before and after treatment. CONCLUSIONS: Sex hormone levels, especially estradiol, varied among females of different ages suffering from depression. Recurrent depression also has a certain effect on sex hormone levels in females. Not only should the age and relapse be considered when studying the sex hormone levels of females with depression, but also attention should be paid to whether the patients have used antidepressants before their sexual hormonal testing.

Efficacy of the quick sequential organ failure assessment for predicting clinical outcomes among community-acquired pneumonia patients presenting in the emergency department.

BACKGROUND: The study aimed to investigate the predictive value of the quick sequential organ failure assessment (qSOFA) for clinical outcomes in emergency patients with community-acquired pneumonia (CAP). METHODS: A total of 742 CAP cases from the emergency department (ED) were enrolled in this study. The scoring systems including the qSOFA, SOFA and CURB-65 (confusion, urea, respiratory rate, blood pressure and age) were used to predict the prognostic outcomes of CAP in ICU-admission, acute respiratory distress syndrome (ARDS) and 28-day mortality. According to the area under the curve (AUC) of the receiver operating characteristic (ROC) curves, the accuracies of prediction of the scoring systems were analyzed among CAP patients. RESULTS: The AUC values of the qSOFA, SOFA and CURB-65 scores for ICU-admission among CAP patients were 0.712 (95%CI: 0.678-0.745, P < 0.001), 0.744 (95%CI: 0.711-0.775, P < 0.001) and 0.705 (95%CI: 0.671-0.738, P < 0.001), respectively. For ARDS, the AUC values of the qSOFA, SOFA and CURB-65 scores were 0.730 (95%CI: 0.697-0.762, P < 0.001), 0.724 (95%CI: 0.690-0.756, P < 0.001) and 0.749 (95%CI: 0.716-0.780, P < 0.001), respectively. After 28 days of follow-up, the AUC values of the qSOFA, SOFA and CURB-65 scores for 28-day mortality were 0.602 (95%CI: 0.566-0.638, P < 0.001), 0.587 (95%CI: 0.551-0.623, P < 0.001) and 0.614 (95%CI: 0.577-0.649, P < 0.001) in turn. There were no statistical differences between qSOFA and SOFA scores for predicting ICU-admission (Z = 1.482, P = 0.138), ARDS (Z = 0.321, P = 0.748) and 28-day mortality (Z = 0.573, P = 0.567). Moreover, we found no differences to predict the ICU-admission (Z = 0.370, P = 0.712), ARDS (Z = 0.900, P = 0.368) and 28-day mortality (Z = 0.768, P = 0.442) using qSOFA or CURB-65 scores. CONCLUSION: qSOFA was not inferior to SOFA or CURB-65 scores in predicting the ICU-admission, ARDS and 28-day mortality of patients presenting in the ED with CAP.

The diagnostic value of homocysteine for the occurrence and acute progression of chronic obstructive pulmonary disease.

BACKGROUND: This study aimed to evaluate whether the Homocysteine (Hcy) level was elevated in chronic obstructive pulmonary disease (COPD) patients and its correlation with the occurrence and acute progression of COPD. METHODS: From November 2014 to November 2015, COPD patients were enrolled from Beijing Chao-yang Hospital, and the the biological and clinical data were collected. These patients were tested in the non-acute exacerbation period and the acute exacerbation period, so they were defined as AECOPD group and Non-AECOPD group. Besides, 50 healthy subjects were recruited and defined as control group. Total plasma Hcy levels (antibodies-online, USA) were determined by enzyme-linked immunosorbent assay. Correlation analysis was used to analyze the correlation between serum Hcy level and ventilatory function. Using ROC curve, the diagnostic value of Hcy for the occurrence and acute progression of COPD was explored. RESULTS: In this study, we found that Hcy levels in the Non-AECOPD group or the AECOPD group were significantly higher than those in the control group (P < 0.001). Meanwhile, compared with the Non-AECOPD group, the Hcy level in the AECOPD group was significantly higher (P < 0.001). In addition, according to the classification of GOLD grade, there was significant difference in the Hcy level among different GOLD grade groups (P < 0.001). The correlation analysis showed that in the AECOPD group and the Non-AECOPD group, Hcy levels presented a negative correlation with FEV1(r < 0). Meanwhile, FEV1% was also negatively correlated with Hcy level (r < 0). ROC curve analysis showed that when the cutoff value was set to 10.8 µg/ml, the specificity, sensitivity and AUC were the best, which were 0.980, 0.800, and 0.945, respectively. Besides, our results showed that when the cutoff value was set to 14.0 µg / ml, the specificity, sensitivity and AUC were the best, which were 0.846, 0.680, and 0.802, respectively. In addition, compared with the prediction of acute progression of COPD, when Hcy level predicted the occurrence of COPD, its specificity (0.980 vs. 0.846, P < 0.001) and sensitivity (0.800 vs. 0.680, P < 0.001) were significantly higher. CONCLUSION: Hcy level is positively correlated with the severity of COPD patients, which has predictive value for the occurrence of COPD and acute progression.

[Causes of emergency dizziness stratified by etiology].

OBJECTIVE: To explore the causes of emergency dizziness stratified to improve the diagnostic efficiency. METHODS: A total of 1 857 cases of dizziness at our emergency department were collected and their etiologies stratified by age and gender. RESULTS: The top three diagnoses were benign paroxysmal positional vertigo (BPPV, 31.7%), hypertension (24.0%) and posterior circulation ischemia (PCI, 20.5%). Stratified by age, the main causes of dizziness included BPPV (n = 6), migraine-associated vertigo (n = 2), unknown cause (n = 1) for the group of <18 years; BPPV (51.5%), migraine-associated vertigo (14.5%) and neurosis (7.3%) for 18-44 years; BPPV (36.8%), hypertension (22.4%) and migraine-associated vertigo (11.2%) for 45-59 years; hypertension (30.8%), PCI (29.8%) and BPPV (22.9%) for 60-74 years; PCI (30.7%), hypertension (28.6%) and BPPV (25.5%) for 75-92 years. BPPV, migraine and neurosis were more common in females while hypertension and PCI predominated in males (all P < 0.05). CONCLUSION: As the main causes of emergency dizziness, BPPV, PCI, hypertension, neurosis and migraine showed the following significant demographic features: BPPV, PCI, hypertension, neurosis and migraine may be the main causes of dizziness. BPPV should be considered initially when vertigo was triggered repeatedly by positional change, especially for young and middle-aged women. And the other common causes of dizziness were migraine-associated vertigo, neurosis and Meniere's disease.Hypertension should be screened firstly in middle-aged and elderly patients presenting mainly with head heaviness and stretching. In elders with dizziness, BPPV is second in constituent ratio to PCI and hypertension.In middle-aged and elderly patients with dizziness, psychological factors should be considered and diagnosis and treatment should be offered timely.

Correlation Analyses Between Serum Interleukin-7, Interleukin-15 and Lactate Provide Insights Into Their Potential Roles in the Regulation of Inflammation in Elderly Septic Patients.

Background: Our previous research have identified Interleukin (IL)-7 and IL-15 as prognostic biomarkers for elderly septic patients, however, little is known about the link between the serum levels of IL-7, IL-15, and lactate as well as their potential roles in the regulation of inflammation in elderly septic patients. Objectives: This study aimed at investigating the link between the serum levels of IL-7, IL-15, and lactate as well as with other factors in elderly septic patients. Design: This is a retrospective study including 129 elderly patients with sepsis who were divided into the survival group (N = 34) and the nonsurvival group (N = 95) and further subgrouped based on the Acute Physiology and Chronic Health Evaluation II (APACHE II) scores. Methods: The baseline data and clinical parameters were recorded within 24 h upon admission. Serum levels of the cytokines were quantified by the Luminex assay. Spearman correlation analysis were performed. Results: Serum levels of IL-6, IL-7, IL-15, and tumor necrosis factor-α (TNF-α) were significantly higher in the nonsurvival group (P < .05). Correlations between serum levels of IL-7 and platelet-derived growth factor-AA (PDGF-AA), as well as correlations between IL-15, IL-6, and TNF-α were confirmed (P < .05). Both the serum levels of lactate and IL-15 correlated with the total counts of platelet (PLT) in the survival subgroup with low APACHE Ⅱ scores while the serum levels of IL-7, IL-15, and total counts of monocytes correlated with each other in the nonsurvival subgroup with different APACHE Ⅱ scores (P < .05). Conclusion: Knowledge of the regulation networks between serum levels of IL-7, IL-15, lactate, and other cytokines may provide insights into potential mechanisms in the modulation of inflammation in elderly septic patients and facilitate more prompt and accurate treatment to reduce the mortality rate.

Characterization and heterologous reconstitution of Taxus biosynthetic enzymes leading to baccatin III.

Paclitaxel is a well known anticancer compound. Its biosynthesis involves the formation of a highly functionalized diterpenoid core skeleton (baccatin III) and the subsequent assembly of a phenylisoserinoyl side chain. Despite intensive investigation for half a century, the complete biosynthetic pathway of baccatin III remains unknown. In this work, we identified a bifunctional cytochrome P450 enzyme [taxane oxetanase 1 (TOT1)] in Taxus mairei that catalyzes an oxidative rearrangement in paclitaxel oxetane formation, which represents a previously unknown enzyme mechanism for oxetane ring formation. We created a screening strategy based on the taxusin biosynthesis pathway and uncovered the enzyme responsible for the taxane oxidation of the C9 position (T9αH1). Finally, we artificially reconstituted a biosynthetic pathway for the production of baccatin III in tobacco.

Pyk2 regulates sepsis-induced lung injury via ferroptosis.

Objectives: The onset of sepsis represents a hyper-inflammatory condition that can lead to organ failure and mortality. Recent findings suggest a potential beneficial effect of protein tyrosine kinase Pyk2 inhibitor on sepsis in a mouse model. In this study, we investigated the regulatory role of Pyk2 inhibitor in ferroptosis and sepsis-associated acute lung injury (ALI). Materials and Methods: A Pyk2 inhibitor or a ferroptosis regulator were injected into mice sustaining sepsis-induced ALI and the effects on lung injury and pro-inflammatory response were evaluated. Clinically, Pyk2 expression was determined in serum samples of patients with sepsis. Further, the association between serum Pyk2 levels and clinical features was determined. Results: Experimental mouse models revealed that treatment with Pyk2 inhibitor TAE226 can significantly alleviate lung injury, downregulate pro-inflammatory responses and decrease markers of ferroptosis, which were induced by LPS. Both upregulation and downregulation of ferroptosis can lead to the loss of TAE226 function, indicating that Pyk2 promotes inflammation via ferroptosis induction. Analysis of clinical samples revealed that the serum Pyk2 levels were significantly increased in patients with sepsis. The serum Pyk2 levels were associated with APACHE2 scores and 30-day mortality. Further, we found a negative correlation between serum Pyk2 and Fe3+ levels, which was consistent with the mechanism identified in the mouse model. Conclusion: Pyk2 inhibitor of ferroptosis is a promising therapeutic candidate against sepsis-related ALI.

Potential Role and Prognostic Value of Interleukin-15 for Mortality Among Elderly Patients with Sepsis.

Background: To investigate the potential role and prognostic value of interleukin-15 (IL-15) in predicting 28-day mortality in elderly patients with sepsis. Methods: According to the Sepsis-3.0 diagnostic criteria for sepsis, elderly patients with sepsis who were admitted to the emergency department of the Shi jingshan branch of Beijing Chaoyang Hospital between October 2021 and June 2022 were enrolled in this retrospective cohort study. After observation for 28 days, patients were divided into a survival group and a nonsurvival group. Samples for laboratory tests, baseline characteristic data, and SOFA and Acute Physiology and Chronic Health Evaluation (APACHE II) scores were collected or recorded within 24 h after admission to the emergency department. Quantitative detection of IL-15 was performed with a Luminex assay. Logistic regression analysis and receiver operating characteristic curve (ROC) analysis were conducted for comparison. Results: In total, 220 elderly patients with sepsis were enrolled, 69 of whom were in the survival group and 151 of whom were in the nonsurvival group at the 28-day interval. Systolic pressure, high-density lipoprotein (HDL), platelets (PLT) and albumin (ALB) were significantly higher in the survival group (P<0.05), while IL-15, SOFA, and APACHE II were significantly higher in the nonsurvival group (P<0.05). IL-15 was an independent risk factor associated with 28-day mortality (OR=1.842, 95% CI [1.323, 2.565]). The area under the receiver operating characteristic curve (AUROC) of IL-15 alone was 0.691 (95% CI [0.618, 0.764]), with a sensitivity of 46.67% and a specificity of 85.81%. The AUROC of the combined IL-15 and SOFA reached 0.880 (95% CI [0.672, 0.812]), for which the sensitivity and specificity were 80.95% and 85.08%, respectively. Conclusion: IL-15 possesses the prognostic value for predicting 28-day mortality in elderly patients with sepsis.

c-Myc-IMPDH1/2 axis promotes tumourigenesis by regulating GTP metabolic reprogramming.

BACKGROUND: Metabolic reprogramming is a hallmark of cancer. Metabolic rate-limiting enzymes and oncogenic c-Myc (Myc) play critical roles in metabolic reprogramming to affect tumourigenesis. However, a systematic assessment of metabolic rate-limiting enzymes and their relationship with Myc in human cancers is lacking. METHODS: Multiple Pan-cancer datasets were used to develop the transcriptome, genomic alterations, clinical outcomes and Myc correlation landscapes of 168 metabolic rate-limiting enzymes across 20 cancers. Real-time quantitative PCR and immunoblotting were, respectively, used to examine the mRNA and protein of inosine monophosphate dehydrogenase 1 (IMPDH1) in human colorectal cancer (CRC), azoxymethane/dextran sulphate sodium-induced mouse CRC and spontaneous intestinal tumours from APCMin/+ mice. Clone formation, CCK-8 and subcutaneous xenograft model were applied to investigate the possible mechanisms connecting IMPDH1 to CRC growth. Co-immunoprecipitation and protein half-life assay were used to explore the mechanisms underlying the regulation of IMPDH1. RESULTS: We explored the global expression patterns, dysregulation profiles, genomic alterations and clinical relevance of 168 metabolic rate-limiting enzymes across human cancers. Importantly, a series of enzymes were associated with Myc, especially top three upregulated enzymes (TK1, RRM2 and IMPDH1) were positively correlated with Myc in multiple cancers. As a proof-of-concept exemplification, we demonstrated that IMPDH1, a rate-limiting enzyme in GTP biosynthesis, is highly upregulated in CRC and promotes CRC growth in vitro and in vivo. Mechanistically, IMPDH2 stabilizes IMPDH1 by decreasing the polyubiquitination levels of IMPDH1, and Myc promotes the de novo GTP biosynthesis by the transcriptional activation of IMPDH1/2. Finally, we confirmed that the Myc-IMPDH1/2 axis is dysregulated across human cancers. CONCLUSIONS: Our study highlights the essential roles of metabolic rate-limiting enzymes in tumourigenesis and their crosstalk with Myc, and the Myc-IMPDH1/2 axis promotes tumourigenesis by altering GTP metabolic reprogramming. Our results propose the inhibition of IMPDH1 as a viable option for cancer treatment.

Reprogramming of palmitic acid induced by dephosphorylation of ACOX1 promotes ß-catenin palmitoylation to drive colorectal cancer progression.

Metabolic reprogramming is a hallmark of cancer. However, it is not well known how metabolism affects cancer progression. We identified that metabolic enzyme acyl-CoA oxidase 1 (ACOX1) suppresses colorectal cancer (CRC) progression by regulating palmitic acid (PA) reprogramming. ACOX1 is highly downregulated in CRC, which predicts poor clinical outcome in CRC patients. Functionally, ACOX1 depletion promotes CRC cell proliferation in vitro and colorectal tumorigenesis in mouse models, whereas ACOX1 overexpression inhibits patient-derived xenograft growth. Mechanistically, DUSP14 dephosphorylates ACOX1 at serine 26, promoting its polyubiquitination and proteasomal degradation, thereby leading to an increase of the ACOX1 substrate PA. Accumulated PA promotes ß-catenin cysteine 466 palmitoylation, which inhibits CK1- and GSK3-directed phosphorylation of ß-catenin and subsequent ß-Trcp-mediated proteasomal degradation. In return, stabilized ß-catenin directly represses ACOX1 transcription and indirectly activates DUSP14 transcription by upregulating c-Myc, a typical target of ß-catenin. Finally, we confirmed that the DUSP14-ACOX1-PA-ß-catenin axis is dysregulated in clinical CRC samples. Together, these results identify ACOX1 as a tumor suppressor, the downregulation of which increases PA-mediated ß-catenin palmitoylation and stabilization and hyperactivates ß-catenin signaling thus promoting CRC progression. Particularly, targeting ß-catenin palmitoylation by 2-bromopalmitate (2-BP) can efficiently inhibit ß-catenin-dependent tumor growth in vivo, and pharmacological inhibition of DUSP14-ACOX1-ß-catenin axis by Nu-7441 reduced the viability of CRC cells. Our results reveal an unexpected role of PA reprogramming induced by dephosphorylation of ACOX1 in activating ß-catenin signaling and promoting cancer progression, and propose the inhibition of the dephosphorylation of ACOX1 by DUSP14 or ß-catenin palmitoylation as a viable option for CRC treatment.

Quantitative and analytical tools to analyze the spatiotemporal population dynamics of microbial consortia.

Microorganisms occupy almost every niche on earth. They play critical roles in maintaining ecological balance, atmospheric C/N cycle, and human health. Microbes live in consortia with metabolite exchange or signal communication. Quantitative and analytical tools are becoming increasingly important to study microbial consortia dynamics. We argue that a combined reductionist and holistic approach will be important to understanding the assembly rules and spatiotemporal population dynamics of the microbial community (MICOM). Reductionism allows us to reconstruct complex MICOM from isolated or simple synthetic consortia. Holism allows us to understand microbes as a community with cooperation and competition. Here we review the recent development of quantitative and analytical tools to uncover the underlying principles in microbial communities that govern their spatiotemporal change and interaction dynamics. Mathematical models and analytical tools will continue to provide essential knowledge and expand our capability to manipulate and control microbial consortia.

Deep Learning-Based Medical Information System in First Aid of Surgical Trauma.

The aim of this study was to explore the application of process reengineering integration in trauma first aid based on deep learning and medical information system. According to the principles and methods of process reengineering, based on the analysis of the problems and causes of the original trauma first aid process, a new set of trauma first aid integration process is established. The Deep Belief Network (DBN) in deep learning is used to optimize the travel path of emergency vehicles, and the accuracy of travel path prediction of emergency vehicles under different environmental conditions is analyzed. DBN is applied to the surgical clinic of the hospital to verify the applicability of this method. The results showed that in the analysis of sample abscission, the abscission rates of the two groups were 2.23% and 0.78%, respectively. In the analysis of the trauma severity (TI) score between the two groups, more than 60% of the patients were slightly injured, and there was no significant difference (P > 0.05). In the comparative analysis of treatment effect and family satisfaction between the two groups, the proportion of rehabilitation patients in the experimental group (55.91%) was significantly better than that in the control group, and the satisfaction of the experimental group (7.93 ± 0.59) was significantly higher than that of the control group (5.87 ± 0.43) (P < 0.05). Therefore, integrating Wireless Sensor Network (WSN) measurement and process reengineering under the medical information system provides feasible suggestions and scientific methods for the standardized trauma first aid.

Evolutionary Principles of Bacterial Signaling Capacity and Complexity.

Microbes rely on signal transduction systems to sense and respond to environmental changes for survival and reproduction. It is generally known that niche adaptation plays an important role in shaping the signaling repertoire. However, the evolution of bacterial signaling capacity lacks systematic studies with a temporal direction. In particular, it is unclear how complexity evolved from simplicity or vice versa for signaling networks. Here, we examine the evolutionary processes of major signal transduction systems in Campylobacterota (formerly Epsilonproteobacteria), a phylum with sufficient evolutionary depth and ecological diversity. We discovered that chemosensory system increases complexity by horizontal gene transfer (HGT) of entire chemosensory classes, and different chemosensory classes rarely mix their components. Two-component system gains complexity by atypical histidine kinases fused with receiver domain to achieve multistep or branched signal transduction process. The presence and complexity of c-di-GMP-mediated system is related to the size of signaling network, and c-di-GMP pathways are easy to rewire, since enzymes and effectors can be linked without direct protein-protein interaction. Overall, signaling capacity and complexity rise and drop together in Campylobacterota, determined by sensory demand, genetic resources, and coevolution within the genomic context. These findings reflect plausible evolutionary principles for other cellular networks and genome evolution of the Bacteria domain. IMPORTANCE Bacteria are capable of sensing and responding to environmental changes by several signal transduction systems with different mechanisms. Much attention is paid to model organisms with complex signaling networks to understand their composition and function, but how a complicated network evolved from a simple one or vice versa lacks systematic studies. Here, we tracked the evolutionary process of each signaling system in a bacterial phylum with robust "eco-evo" framework and summarized the general principles of signaling network evolution. Our findings bridge the gaps in bacterial signaling capacity from highly sophisticated to extremely streamlined, shedding light on rational design of genetic circuitry. This study may serve as a paradigm to examine the complex construction of other cellular networks and genome evolution.

Advanced genome-editing technologies enable rapid and large-scale generation of genetic variants for strain engineering and synthetic biology.

Targeted genome editing not only improves our understanding of fundamental rules in life sciences but also affords us versatile toolkits to improve industrially relevant phenotypes in various host cells. In this review, we summarize the recent endeavor to develop efficient genome-editing tools, and emphasize the utility of these tools to generate massive scale of genetic variants. We categorize these tools into traditional recombination-based tools, and more advanced CRISPR as well as RNA-based genome-editing tools. This diverse panel of sophisticated tools has been applied to accelerate strain engineering, upgrade biomanufacturing, and customize biosensing. In parallel with high-throughput phenotyping and AI-based optimization algorithms, we envision that genome-editing technologies will become a driving force to automate and streamline biological engineering, and empower us to address critical challenges in health, environment, energy, and sustainability.

Prevalence of post-traumatic stress disorder after earthquakes among the elderly in China: A meta-analysis.

BACKGROUND: The study aims to investigate the occurrence of post-traumatic stress disorder (PTSD) after earthquakes among the elderly. METHODS: Data from cross-sectional studies focusing on the prevalence of PTSD after earthquakes among the elderly were collected from PubMed, EMBASE, Cochrane Library, and China National Knowledge Infrastructure in December 2019. The search terms included post-traumatic stress disorder, earthquake, and elderly. This study used Review Manager 5.0 to evaluate the impact of the results. In addition, forest plots, sensitivity analysis, and bias analysis were carried out on the included articles. The combined estimate of the risk ratio and the standard deviation of the 95% confidence interval (95% CI) were measurements of the size of the effect. RESULTS: There were 4,834 patients included from 10 eligible studies. The sample sizes of PTSD group and non-PTSD group were 1,277 and 3,557, respectively. The meta-analysis showed that the overall occurrence of PTSD after earthquakes among the elderly was 0.25; the occurrence in females was higher than that in males, and the occurrence in the same province indicated little difference (Wenchuan city 0.25 and Ya'an city 0.24). CONCLUSIONS: After earthquakes, the occurrence of PTSD is higher among the elderly than among other age groups, and higher among the females than among the males, while there is little difference among different areas within the same province. This indicated that prioritized specific psychological interventions should be provided to the aged and the females.